Regio- and Stereoselective Ring Opening of Enantiomerically Enriched 2-Aryl Oxetanes and 2-Aryl Azetidines with Aryl Borates

Abstract

The regioselective ring opening of 2-aryl-substituted four-membered heterocyclic rings with phenols, including catechol, was achieved by the use of aryl borates in mild and neutral reaction conditions without the aid of any transition metal catalysts. While N-alkyl azetidines were found not to be reactive, optically active N-tosyl azetidines gave the corresponding beta-aryloxy amines in a racemic form, thus indicating the considerable carbocationic character of the transition state. The introduction of a hydroxyl group in the azetidine ring (i.e., an azetidinol), able to anchor the aryl borate and to direct the subsequent nucleophilic delivery, was shown to determine the ring-opening process with predominant inversion of configuration. When enantiomerically enriched 2-aryl oxetanes were used, the reduced extent of racemization observed (up to 93:7 er) was rationalized by an intramolecular delivery through a six-membered transition state, giving beta-aryloxy alcohols with a predominant retention of configuration (i.e., a syn-stereoselective ring opening). The aryloxy alcohols obtained, endowed with suitable functionalities, can be cyclized to give access to enantiomerically enriched 2-aryl-1,5-benzodioxepins.

Oxetanes as Versatile Elements in Drug Discovery and Synthesis

“…Enantiomerically enriched 2-phenyloxetane (18) can be opened regio-and stereoselectively with various aryl borates to give b-aryloxy alcohols 93 (Scheme 16). [62] It was found that the ring-opening reaction proceeded largely with retention of configuration.…”

A Simple, Effective Boron‐Halide Ethoxylation Catalyst

“…[13] Transition states with similar structures have been proposed to account for related modes of epoxide activation mediated by borates. [14] This mechanism accounts for the deuterium labelling results. As exemplified in Scheme 2, activation of non-labelled EO with bromide and a labelled ester yields intermediates such as borate anion C bearing d 0 -and d 4 -bromoethyl groups.…”

Ultrafast Iron‐Catalyzed Reduction of Functionalized Ketones: Highly Enantioselective Synthesis of Halohydrines, Oxaheterocycles, and Aminoalcohols

“…[23] Given the importance of chiral 1,4-dioxanes as building blocks in natural products and pharmaceutical agents along with the successful reduction of the haloketones 5 and 8,w e explored synthetic strategies for this class of products based on the methods developed in this work. [23] Given the importance of chiral 1,4-dioxanes as building blocks in natural products and pharmaceutical agents along with the successful reduction of the haloketones 5 and 8,w e explored synthetic strategies for this class of products based on the methods developed in this work.…”

“…Zuschriften up produced the related chiral oxetanes 7a-c and tetrahydrofurans 10 a-c with identical selectivities.W hereas all ghalo derivatives could smoothly be converted into the tetrahydrofuran derivatives by direct addition of K 2 CO 3 / MeOH to the reaction mixture,incomplete cyclization of the boronic esters precluded such an in situ approach in the case of the oxetanes 7a-c.T herefore,t he b-halohydrines 6a-c were isolated prior to ring closure with KO t Bu/THF. [23] Given the importance of chiral 1,4-dioxanes as building blocks in natural products and pharmaceutical agents along with the successful reduction of the haloketones 5 and 8,w e explored synthetic strategies for this class of products based on the methods developed in this work. To this end, the previously unknown reduction of chloro keto ethers,which in turn are readily available by Grignard addition to 2-chloro ethoxy acetonitrile, [24] was thought to provide ac onvenient starting point for the preparation of such oxaheterocycles.…”